Alzheimer's disease (AD) is a devastating disease, with an insidious onset and relentless progress. It produces distressing changes in memory, thought, perception, and often behavior. These changes increasingly impact the patient's daily life, reducing functional independence, until ultimately, the patients are entirely dependent on others. AD is a progressive disease, where the neurons in the brain gradually degenerate. One of the consequences of this degeneration of the brain is an increased level of cellular waste between the neurons, known as plaques and tangles. As AD progresses, the physical volume of the brain decreases as more and more neurons die. AD is the most common cause of dementia, accounting for up to 80% of all cases. Studies show that as many as 5% of all people above the age of 65 will develop AD. The number of Americans living with AD is growing rapidly. An estimated 5.7 million Americans of all ages have Alzheimer's disease in 2018. Therefore, identification of molecular regulators required to improve cognition, promote cell survival and facilitate neuroprotectants as new therapeutics is essential. Endoplasmic reticulum (ER) protein sigma-1 receptor (S1R) represents a unique chaperone activity in the central nervous system, and it exerts a potent influence on a number of neurotransmitter systems. S1R is distinct from GPCRs and ionotropic receptors and is expressed in neurons in multiple brain regions in post-mortem human brains. S1R plays a modulatory role in biological mechanisms associated with neurodegeneration. S1R ligands activation is known to improve cognition, promote cell survival and facilitate release of the neuroprotectant BDNF. In addition, PET Imaging studies with [11C]SA4503, a specific S1R ligand, have demonstrated that the S1R is widely distributed in normal and AD human brains indicating that our target receptor is present in the disease state. More important is that our proposed target receptor is easily detected in AD brain and our preliminary efficacy data of EPGN644 suggesting that the S1R is a suitable target for novel AD therapies. The research plan presented herein realizes this objective and combines the drug discovery and development expertise of Epigen Biosciences towards commercialization with the in vivo pharmacology expertise of Prof. Dave Morgan and Prof. Kevin Nash?s group at Michigan State University and the University of South Florida, respectively.